The two major hallmarks of Alzheimer's disease are beta-amyloid deposition and neuronal cell death. Roughly half of early-onset familial Alzheimer's disease is caused by mutations in the presenilin genes, PS1 and PS2. FAD-linked presenilin mutations are responsible for both the production of an elevated ratio Abeta40: Abeta42 and an increased susceptibility to apoptosis. To elucidate the biological function of presenilins, efforts have been made to identify molecules that interact with presenilins. We have recently found that the endogenous C-terminal fragment of PS1 (PS1 -CTF) interacts with endogenous beta-catenin in H4 neuroglioma cells and we report here that GSK3beta is also recruited in the same complex. Since GSK3beta is responsible for beta-catenin phosphorylation and degradation, it is possible that beta-catenin/GSK3beta/PS1 complex might be involved in the regulation of free beta-catenin level that is a limiting factor for beta-catenin signaling. To date, opposite effects of PS1 FAD-linked mutations have been reported on the regulation of beta-catenin level. Contradictory effect of PS1 FAD-linked mutations have been also reported for PS1/GSK3beta binding: increased PS1 GSK3beta binding or defect of GSK3beta recruitment. The goal of the present proposal is to further investigate the role of PS1 FAD-linked mutations on GKS3beta activity and beta-catenin regulation. The identifications of alterations in GSK3beta/beta-catenin pathway will be the basis for a future research projected (RO1) aimed to study how such alterations may affect Abeta production and/or neuronal cell death in Alzheimer's disease.